Peptide YY (PYY), a newly discovered ileocolonic peptide, is released by nutrients in the proximal and distal intestine and inhibits pancreatic secretion. However, it is not clear whether PYY can be released in the absence of nutrients in the intestine or whether a physiological role exists for endogenous PYY in negative feedback regulation of pancreatic secretion by pancreatic proteases. In the present study we measured plasma PYY concentrations and determined the effects of anti-PYY serum during stimulation of pancreatic secretion by pancreatic juice diversion (PJD). The effect of SMS 201-995 (SMS; an analog of somatostatin), another inhibitor of pancreatic secretion, on regulation of PYY release induced by PJD was also investigated. Male Wistar rats equipped with pancreatic, biliary, duodenal, and jugular venous cannulas were studied 4-6 days postoperatively. After 90 min of basal collection, pancreatic juice was diverted for 4 h with or without infusion of SMS (2 micrograms/kg.h), given either iv or intraduodenally (ID). Plasma PYY concentrations were significantly increased from a basal level of 177 +/- 15 pg/ml to a peak level of 328 +/- 43 pg/ml 2 h after PJD. These increases in PYY concentration paralleled those in pancreatic protein and fluid outputs. Both iv and ID infusion of SMS during the first 2 h of PJD markedly decreased the plasma PYY concentration to 134 +/- 27 pg/ml and 156 +/- 19 pg/ml, respectively; the total incremental PYY release during 4 h of PJD was inhibited by 100% and 84% by iv and ID SMS, respectively. One milliliter of anti-PYY serum given iv significantly augmented the increment in protein and fluid output during PJD. These results suggest that endogenous PYY released by PJD may play a physiological role in negative feedback regulation of pancreatic secretion in rats.